Applicants also claim priority under 35 U.S.C. xc2xa7119(a-d) of Italian patent application no. MI99A 002174, filed Oct. 18, 1999, which is hereby incorporated by reference
This invention relates to benzopyran derivatives, to pharmaceutical compositions containing them and to uses for such derivatives and compositions.
Flavoxate, 3-methyl-4-oxo-2-phenyl-8-(2,N-piperidinylethoxycarbonyl)-4H-1-benzopyran, has the formula: 
and is used as a pharmaceutical agent for urinary-tract disturbances as it possesses a smooth-muscle relaxing activity attributable to its calcium antagonist activity. This activity is exerted on the bladder-neck smooth muscles or can be related to an effect on the micturition centre in the central nervous system (Guarneri L. el al., Drugs of Today, 30:91-98, 1994).
U.S. Pat. No. 5,403,842, Leonardi et al., and its continuations in part (U.S. Pat. No. 5,474,994, Leonardi et al., and U.S. Pat. No. 5,605,896, Leonardi et al.) claim more complex amino functions in place of the piperidinyl group of flavoxate. Further claimed changes include alternatives to the ethoxycarbonyl group which links the amino moiety to position 8 of the benzopyran ring, alternative substitutions at positions 2, 3, 6 and 7 of the benzopyran ring, replacement of the ring heteroatom by a sulphur atom or by a sulphinyl or sulphonyl group, or by a nitrogen atom or an amino group, and/or hydrogenation at position 2-3 of the benzopyran ring. Further variations of the heterocyclic ring were also described. These structural variations gave the new compounds the ability to interact with different biological systems, as supported by the affinity of the new compounds for the xcex11-adrenergic and 5HT1A-serotoninergic receptors. Flavoxate is practically devoid of affinity for these receptors. One of the most interesting of the compounds of U.S. Pat. No. 5,403,842, Leonardi et al., was Compound A (Ex. 11). 
The compounds of the present invention retain the 3-methyl-4-oxo-8-[(xcfx89-(4-phenyl-1-piperazinyl)alkylcarbamoyl]-4H-1-benzopyran structure of Compound A, but introduce alternative substituents in place of the phenyl group at position 2 of the benzopyran ring and new patterns of substitution for the phenyl group linked to the piperazine ring. These new compounds are endowed with selective antagonistic activity for the xcex11 receptor (in particular if compared to affinity for the 5-HT1A receptor) and are able to reduce the contractility of prostatic urethra in mammals with little or no effect on blood pressure. This activity profile suggests the safer use of the compounds of the invention in the therapy of obstructive syndromes of the lower urinary tract, including benign prostatic hyperplasia (BPH), female lower urinary tract symptoms (LUTS), and neurogenic lower urinary tract dysfunction (NLUTD), without side effects associated with hypotensive activity. Some of the new compounds also have a longer duration of action on the urethra than Compound A.
The invention describes compounds of the general formula I: 
wherein
R is selected from the group consisting of a phenyl, alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group;
R1 is selected from the group consisting of an alkyl, alkoxy, polyfluoroalkoxy, hydroxy and trifluoromethanesulphonyloxy group;
each of R2 and R3 independently is selected from a group consisting of a hydrogen, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano and carbamoyl group; and
n is 0, 1 or 2;
with the proviso that, if R represents a phenyl group and both R2 and R3 represent hydrogen and/or halogen atoms, then R1 represents a polyfluoroalkoxy or trifluoromethanesulphonyloxy group.
The invention also includes the N-oxides and pharmaceutically acceptable salts of these compounds.
When R does not represent a phenyl group, each of R2 and R3 preferably independently represents a hydrogen or halogen atom or a polyfluoroalkoxy group.
Alkyl and alkoxy groups preferably have from 1 to 4 carbon atoms; complex groups such as alkoxycarbonyl, alkylcarbonyl, alkylcarbamoyl, dialkylcarbamoyl, polyfluoroalkyl, polyfluoroalkoxy and alkoxycarbonylamino, are preferably construed accordingly. Preferred polyfluoroalkoxy groups are trifluoromethoxy and 2,2,2-trifluoroethoxy. The preferred value for n is 1.
Further preferred is where R is selected from the group consisting of phenyl, alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino; R1 is selected from the group consisting of alkoxy and hydroxy; each of R2 and R3 is independently selected from the group consisting of hydrogen, halogen, polyfluoroalkyl and carbamoyl; and n=0, 1 or 2.
Further preferred is where R is selected from the group consisting of carbamoyl, alkylcarbamoyl and dialkylcarbamoyl; R1 is selected from the group consisting of alkoxy, polyfluroalkoxy, hydroxy and trifluoromethanesulphonyloxy; each R2 and R3 is independently selected from the group consisting of hydrogen, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano and carbamoyl; and n=0, 1 or 2.
Further preferred is where R is carbomoyl; R1 is selected from the group consisting of alkoxy; polyfluoroalkoxy, hydroxy, and trifluoromethanesulphonyloxy; each R2 and R3 is independently selected from the group consisting of hydrogen, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano and carbamoyl; and n=0, 1 or 2.
The compounds of the invention include those compounds where, independently, R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group, R1 is selected from a group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group, R2 is selected from the group consisting of hydrogen and fluorine, R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or 2.
Other compounds within the invention are those compounds with combinations of substituents where, together, R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group and R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group; or R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group and R2 is selected from the group consisting of hydrogen and fluorine; or R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or 2.
Compounds of the invention also include those compounds with combinations of substituents where, together, R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group and R2 is selected from the group consisting of hydrogen and fluorine; or R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or 2.
Also included within the invention compounds with combinations of substituents where, together, R2 is selected from the group consisting of hydrogen and fluorine and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or 2.
The invention also includes compounds having combinations of substituents where, together, R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group, R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group and R2 is selected from the group consisting of hydrogen and fluorine; or R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group, R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; or R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group, R2 is selected from the group consisting of hydrogen and fluorine and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl group; and n is 0, 1 or 2.
The compounds of the invention also include those having combinations of substituents where, together, R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group, R2 is selected from the group consisting of hydrogen and fluorine and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl; and n is 0, 1 or 2.
The compounds of the invention also include those having combinations of substituents where, together, R is selected from the group consisting of an alkoxycarbonyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano and alkoxycarbonylamino group, R1 is selected from the group consisting of methyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy and trifluoromethanesulphonyloxy group, R2 is selected from the group consisting of hydrogen and fluorine and R3 is selected from the group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethoxy, cyano and carbamoyl.
The invention further provides pharmaceutical compositions comprising a compound of the general formula I or a N-oxide or pharmaceutically acceptable salt of such a compound in admixture with a pharmaceutically acceptable diluent or carrier. Preferences are as outlined above for the compounds of the invention.
In another aspect, the present invention is directed to methods for preventing contractions (including noradrenaline-mediated contractions) of the urethra and lower urinary tract, without substantially affecting blood pressure, by administering one or more selected compounds of the general Formula I to a mammal (including a human) in need of such treatment in an amount or amounts effective for the particular use.
In yet another aspect, the invention is directed to methods for blocking xcex11 receptors by exposing said receptors (e.g. by delivery to the environment of said receptors, by addition to an extracellular medium, or by administering to a mammal possessing said receptors) an effective amount of a compound of the invention, in this way relieving diseases associated to overactivity of said receptors.
The very high uroselectivity of the compounds of this invention has been tested in the dog model described in Example 28, where their efficacy in antagonizing the contractions of prostatic urethra in the presence of very limited effects on blood pressure has been shown, in comparison to Compound A and to other well know xcex11 antagonists, prazosin and terazosin. Accordingly, it is a primary object of the present inventi to provide a method of treating BPH which avoids any undue side effect due to acute hypotension (i.e., limited effects on blood pressure).
As used herein, xe2x80x9climited effect on blood pressurexe2x80x9d and xe2x80x9cwithout substantial effect on blood pressurexe2x80x9d are defined as effects on blood pressure that are without clinical significance. In experimental animals, xe2x80x9climitedxe2x80x9d and xe2x80x9cwithout substantialxe2x80x9d effects on blood pressure are defined as lowering blood pressure by about 10% or less, compared to control animals. In humans, xe2x80x9climitedxe2x80x9d and xe2x80x9cwithout substantialxe2x80x9d effects on blood pressure are defined as effects wherein diastolic blood pressure is reduced by less than about 5 mm Hg.
It is another object of the present invention to provide pharmaceutical compositions comprising 2-substituted benzopyran-8-carboxamide derivatives which are very potent xcex11-adrenoceptor antagonists, which compositions are effective for the treatment of BPH, optionally including a carrier or diluent.
It is another object of the present invention to provide a method of treating BPH using 2-substituted benzopyran-8-carboxamide derivatives which are active as xcex11-adrenoceptor selective antagonists.
Another aspect of the invention is the use of new compounds for lowering intraocular pressure, inhibiting cholesterol biosynthesis, treatment of cardiac arrhythmia and erectile dysfunction, and reducing sympathetically-mediated pain.
It is understood that xe2x80x9csympathetically-mediatedxe2x80x9d is defined as any physiological sensation, condition or response that depends upon any component of the sympathetic nervous system, can be modulated by the action of any component of the sympathetic nervous system, or can be affected by treatment of any component of the sympathetic nervous system.
A further object of the present invention is the release of compounds of the present invention or pharmaceutical compositions containing compounds of the present invention in the environment of xcex11 adrenergic receptors wherein said release is effected by administering compounds of the present invention or pharmaceutical compositions containing compounds of the present invention to a mammal including a human possessing said receptors.
A further object of the present invention is the method of treatment of a patient suffering from benign prostatic hyperplasia, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from excessive intraocular pressure, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from cardiac arrhythmia, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from erectile dysfunction, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from sexual dysfunction, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method for inhibiting cholesterol biosynthesis, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method for reducing sympathetically mediated pain, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method for the treatment of lower urinary tract symptoms (LUTS), which include but are not limited to filling symptoms, urgency, incontinence and nocturia, as well as voiding problems such as weak stream, hesitance, intermittency, incomplete bladder emptying and abdominal straining, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment, optionally further comprising the inclusion of an anticholinergic compound which may be selected from the group consisting of tolterodine, oxybutinin, darifenacin, alvameline and temiverine.
A further object of the present invention is the method for the treatment of neurogenic lower urinary tract dysfunction (NLUTD), the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to the patient, optionally further comprising the inclusion of an anticholinergic compound which may be selected from the group consisting of tolterodine, oxybutinin, darifenacin, alvameline and temiverine.
A further object of the present invention is the treatment of LUTS in females which include but are not limited to filling symptoms, urgency, incontinence, and nocturia as well as voiding problems such as weak stream, hesitance, intermittency, incomplete bladder emptying, and abdominal straining, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a woman in need of such treatment, optionally further comprising the inclusion of an anticholinergic compound which may be selected from the group consisting of tolterodine, oxybutinin, darifenacin, alvameline and temiverine
Other features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and claims.
All patents, patent applications, and literature references cited in this application are incorporated by reference in their entirety.
It is understood that all compounds described, listed and represented herein are meant to include all enantiomers or mixtures of enantiomers, hydrates, solvates, polymorphs and pharmaceutically acceptable salts thereof.
The adrenergic antagonistic activity of the compounds of the invention renders them useful as agents acting on body tissues particularly rich in xcex11 adrenergic receptors (such as prostate, urethra and bladder). Accordingly, the anti-adrenergic compounds within the invention, established as such on the basis of their receptor binding profile, can be useful therapeutic agents for the treatment, for example, of micturition problems associated with obstructive disorders of the lower urinary tract, including but not limited to benign prostatic hyperplasia (BPH).
BPH is a progressive condition, which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urinary stream and hesitancy or delay in starting urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the ageing male population. BPH is observed in approximately 70% of males over the age of 70. Currently, the specific method of choice for treating BPH is surgery. A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
xcex1-Adrenergic receptors (McGrath, J. C. et al., Med. Res. Rev. 9:407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important targets for controlling many physiological functions and, thus, represent important objectives for drug development. In fact, many xcex1 adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin, tamsulosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). xcex1-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter noradrenaline, and antagonists (phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin and tamsulosin are antagonists), which act to block the effects of noradrenaline. Many of these drugs are effective, but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effect).
The above reported agonists are selective for the xcex12 adrenergic receptor whereas most antagonists are selective for the xcex11 adrenoceptor, with the exception of tamsulosin which shows a comparable affinity also for the 5-HT1A receptor. Many of the cited xcex11 antagonists are currently used for the therapy of BPH but, due to their poor uroselectivity, they are liable to cause cardiovascular side effects.
Recent pharmacological, biochemical and radioligand-binding studies evidenced three different xcex11-receptor subtypes with a high affinity for prazosin, namely xcex11A-(xcex11a-), xcex11B-(xcex11b-) and xcex11D-(xcex11d-), with lower case subscripts being used for recombinant receptors and upper case subscripts for receptors in native tissues (Hieble P. et al., Pharmacol. Rev., 47: 267-270, 1995). In functional studies xcex11 receptors with a low affinity for prazosin have also been identified and termed xcex11L receptors (Flavahan et al., Trends Pharmacol. Sci., 7: 347-349, 1986; Muramatsu et al., Pharmacol. Comm., 6: 23-28, 1995).
Several studies have demonstrated the presence of these xcex11-adrenergic receptor subtypes in the lower-urinary-tract tissues (Andersson K. E., xe2x80x9c4th International Consultation in Benign Prostatic Hyperplasia (BPH)xe2x80x9d, Paris, Jul. 2-5, 1997, pages 601-609).
Several studies have shown that the human prostate receives innervation from both the sympathetic and parasympathetic nervous systems.
The adrenergic nerves are considered responsible for prostatic smooth muscle tone by releasing noradrenaline, stimulating contraction-mediating xcex11-adrenoceptors. Approximately 50% of the total urethral pressure in BPH patients may be due to xcex11-adrenoceptor-mediated muscle tone. Functional studies have indicated the occurrence of important adrenoceptor functions in prostatic adenomatous and capsular tissue. Clinical studies with the prototypical xcex11-adrenoceptor selective antagonist, prazosin, enforced the key role of xcex11 adrenoceptors in the control of prostatic smooth-muscle tone. This was also confirmed in the laboratory by studies showing that, although both xcex11 and xcex12 adrenoceptors can be identified within the human prostate, the contractile properties are mediated primarily by xcex11 adrenoceptors. Many clinical investigations have confirmed that xcex11-adrenoceptor blockade relieves lower-urinary-tract symptoms (LUTS), both of irritative and obstructive type, in patients with BPH.
Lower urinary tract symptoms (LUTS) also develop in women as they age. As in men, LUTS in women includes both filling symptoms such as urgency, incontinence, and nocturia, and voiding symptoms, such as weak stream, hesitancy, intermitency, incomplete bladder emptying and abdominal straining. That both men and women experience a similar high prevalence of filling and voiding LUTS suggests that at least part of the underlying etiology may be identical. In a recent study, an xcex11-antagonist was reported to reduce LUTS in women to a greater extent than an anticholinergic (Serels, S. and Stein, M., Neurology and Urodynamics 17: 31-36, 1998). The authors concluded that there appeared to be a role for xcex11-antagonists in treating LUTS in women. The possible mechanisms implicated to explain these results are: a) dysfunction of the bladder neck and urethra, causing functional outlet obstruction, analogous to BPH-induced outlet obstruction, with secondary detrusor overactivity; and b) increased xcex11-adrenoreceptor activity in the detrusor, causing frequency and urgency. On these bases, xcex11-antagonists are used in clinical practice to treat LUTS in women. The results of Serels also indicate that the combined administration of xcex11-antagonists and anticholinergics can have improved efficacy in treatment of LUTS, as suggested by Fitzpatrick (International British J. Urol. 85, Supp. 2: 1-5, 2000).
Another possible use of xcex11-antagonists is the management of neurogenic lower urinary tract dysfunction (NLUTD), as can be caused by neurological disease or trauma. NLUTD may lead to debilitating symptoms and serious complications, including increased urinary frequency, incontinence, voiding difficulty, recurrent upper urinary tract infections, and upper urinary tract deterioration. Management of NLUTD is indicated to preserve renal function and avoid urological complications. Administration of xcex11-antagonists may benefit patients with NLUTD by facilitating urine storage by alleviating high detrusor pressure during bladder filling, which is evidenced by poor bladder compliance and detrusor hyperreflexia. In both animal models and patients with spinal cord injury resistant to anticholinergics, xcex11-antagonists improved bladder compliance. (Serels, ibid.; Fitzpatrick, ibid.; Kakizaki, M. et al., Brit. J. Urol International 85, Supp. 2: 25-30, 2000; Sundin, T. et al., Invest. Urol. 14: 322-328, 1977; McGuire et al., Neurology and Urodynamics 4: 139-142, 1985; Swierzewski, S. J. et al., J. Urol. 151: 951-954, 1994).
Two distinct xcex11-adrenoceptor subtypes have been suggested to be present in the human prostate, one with high (xcex11H) and one with low (xcex11L) affinity for prazosin. All three high-affinity xcex11-adrenoceptor subtypes found in molecular cloning studies have been identified in prostatic stromal tissue. The xcex11a subtype was found to be the dominant, representing about 60-85% of the xcex11-adrenoceptor population. Recent findings suggest that there may be differences in subtype populations between normal and hyperplastic prostates, the ratios between the subtypes xcex11a:xcex11b:xcex11d being 85:1:14 in BPH tissue and 63:6:31 in non-BPH tissue.
The xcex11A adrenoceptor was reported to mediate the contractile response of the human prostate in vitro. Ford et al. (Br. J. Pharmacol. 114: 24 P, 1995), found that the xcex11A adrenoceptor may not mediate contractile responses to noradrenaline, and suggested as a candidate the xcex11L adrenoceptor. Findings by Kenny et al. (Br. J. Pharmacol. 118: 871-878, 1996) support the view that the xcex11L adrenoceptor, which appears to share many of the characteristics of an xcex11A adrenoceptor, mediates the contractile response of the human prostate.
On the other hand, it has also been suggested that the xcex11A and xcex11L adrenoceptors may represent distinct pharmacological forms of the same receptor.
In the female urethra, mRNA for the xcex11 subtype was predominant and autoradiography confirmed the predominance of the xcex11A adrenoceptor (Andersson K. E., Brit. J. Urol. Intl. 85, Supp. 2: 12-18, 2000). The xcex11A and xcex11D subtypes are reported to be present in the human detrusor, with the latter subtype predominant (Malloy B. et al., J. Urol. 160: 937-943, 1998). Accordingly, the evidence that xcex11 adrenoreceptor antagonists are useful in treating lower urinary tract symptoms of both prostatic and non-prostatic origin in both males and females can be used to support the usefulness of the compounds of the present invention in treating such symptoms regardless of whether they are of obstructive origin or not and regardless of the sex of the patient.
The affinity of the compounds of the invention for each receptor can be assessed by receptor binding assays, for example as follows:
(1) xcex11-adrenergic-receptor subtypes: using the specific ligand 3H-prazosin, according to Testa R. et al., Pharmacol. Comm. 6: 79-86, 1995; Cotecchia S. et al., Proc. Natl. Acad. Sci. USA, 85: 7159-7163, 1988; Furchgott R. E., Handbook of Experimental Pharmacologyxe2x80x94New Series, 283-335, 1972; Michel M. C. et al., Brit. J. Pharmacol. 111: 533-538, 1994; Schwinn D. A. et al., J. Biol. Chem. 265: 8183-8189, 1990; Testa R. et al., Eur. J. Pharmacol. 249: 307-315, 1993.
(2) 5HT1A-serotonergic receptors: using the specific ligand 3H-8-OH-DPAT according to Fargin et al., Nature 335: 358-360, 1988; Kobilka B. K. et al., Nature 329: 75-79, 1987; Cullen B. R., Meth. Enzym. 152: 684-704, 1987; Gozlan H. et al., J. Receptor Res. 7: 195-221, 1987.
The xcex11L adrenergic receptor is not yet cloned and, therefore, the functional affinity of the compounds of the invention for this subtype can be assessed by using an isolated organ preparation as reported by Testa R. et al. (J. Pharmacol. Exp. Ther., 281, 1284-1293, 1997).
In vitro testing of compounds of this invention on the above receptors is described in Ex.s 26 and 27 below.
The drugs having xcex11-adrenergic antagonistic activity currently used for the symptomatic therapy of BPH are poorly subtype selective and subject to cause relevant side effects due to their hypotensive activity.
Thus there is still a need for selective a:, antagonists which do not subject the BPH patient to the side effects, especially the cardiovascular side effects, of said treatments. The very high uroselectivity of the compounds of this invention has been tested in the dog model described in Ex. 28, where their efficacy in antagonizing the contractions of prostatic urethra in the presence of very limited effects on blood pressure has been shown, in comparison to Compound A and to other well know ax, antagonists, prazosin and terazosin.
In addition, the longer duration of action of the compounds of the invention has been assessed in the dog model in Ex. 29.
Other features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and appended claims.
The compounds according to the invention may generally be prepared as follows: 
The condensation of acids 1 with xcfx89-aminoalkylamino derivatives 2 (Scheme 1) can be carried out in the presence or absence of a coupling agent (e.g. dicyclohexylcarbodiimide or diethyl cyanophosphonate) optionally in the presence of a promoting agent (e.g. N-hydroxysuccinimide, 4-dimethylaminopyridine or N,Nxe2x80x2-carbonyldiimidazole) in a polar aprotic or chlorinated solvent (e.g., dimethylformamide or chloroform) at xe2x88x9210/140xc2x0 C. (Albertson N. F., Org. React. 12: 205-218, 1962; Doherty A. M. et al., J. Med. Chem., 35: 2-14, 1992; Ishihara Y. et al., Chem. Pharm. Bull., 39: 3236-3243, 1991).
In some cases the intermediate esters or amides (such as N-hydroxysuccinimidyl esters or acyl imidazolides) can be isolated and further reacted with 2 to be transformed into the corresponding amides (I) in polar aprotic or chlorinated solvent at 10/100xc2x0 C. Another intermediate which can be used is the mixed anhydride obtainable by reacting 1 with an alkyl chloroformate in the presence of a tertiary amine (e.g., triethylamine or N-methylmorpholine) followed by addition of 2 at 0-80xc2x0 C., optionally a promoting agent (e.g., 1-hydroxypiperidine) may be added before the amine addition (Albertson N. F., Org. React. 12: 157, 1962).
Alternatively the condensation can be carried out without solvent at 150-220xc2x0 C. (Mitchell J. A. et al., J. Am. Chem. Soc. 53: 1879, 1931) or in high-boiling ethereal solvents (e.g., diglyme). The condensation can also be performed through isolation of reactive derivatives of 1 such as acyl halides. Preparation of acyl halides of compounds of formula 1 and reactions with amines 2 to form amides is well documented in the literature and known to people skilled in the art.
Also less reactive derivatives of 1 can be used, such as alkyl esters, which, in turn, can be converted into I in the presence of a condensing agent (e.g., trimethylaluminium) in an aprotic and/or chlorinated solvent (e.g., hexane, dichloromethane) at xe2x88x9210/80xc2x0 C., or without solvents at 80-180xc2x0 C. (Weinreb S. M. et al., Tetrahedron Lett. 4171, 1977; Lipton M. F. et al., Org. Synth. 59: 49, 1979).
By the same methods of condensation reported above and using H2NCH2(CH2)nCH2X (with X=halogen or OH) as a reagent, 1 can be converted into the corresponding derivatives 3. Compounds 3 ( with X=leaving group such as halogen, alkylsulphonyloxy or arylsulphonyloxy group) can be subsequently reacted with the appropriate phenylpiperazine 7 directly or by two sequential reactions, in the case of Xxe2x95x90OH derivatives, which include conversion of the alcoholic group into a suitable leaving group by methods well known to those skilled in the art. The nucleophilic substitution on 3 to give I is preferably, but not necessarily, carried out at a temperature within the range of 20-160xc2x0 C. in a polar solvent such as dimethylformamide, acetonitrile, methanol, or without solvent, usually in the presence of a base such as potassium carbonate. See also Gibson""s chapter in Patai, The Chemistry of the Amino Group, p. 45, Wiley lnt. Sci., N.Y., 1968.
The preparation of compounds 2 which are not commercially available is disclosed in the literature and is well known to those skilled in the art and is usually carried out performing nucleophilic substitution of a phenylpiperazine 7 on an N-(xcfx89-haloalkyl)phthalimide or suitable xcfx89-haloalkylnitrile or amide by the method illustrated above. Standard phthalimido-group deprotection and reduction of the amido or cyano group provide compounds 2.
Alternatively, addition of 7 to xcex1,xcex2-unsaturated alkylamides or nitriles (Michael reaction; March J., Advanced Organic Chemistry, 4th edition, J. Wiley, ed., page 760, 1992) can be used, followed by reduction of the amido or cyano groups. The addition of xcex1,xcex2-unsaturated alkylamides or nitrile can be carried out in solvents such as ethanol, acetonitrile, toluene, dimethylformamide or a chlorinated solvent at a temperature between 20-25xc2x0 C. and the reflux temperature in the presence or absence of catalysts such as triethylamine, 4-dimethylaminopyridine. 
The compounds 1 of the invention in which R represents an alkylcarbonyl group (Scheme 2) can be synthesized starting from 2-hydroxy-3-(1-propenyl)propiophenone which is condensed with excess diethyl oxalate in the presence of a base (e.g., sodium ethoxide, sodium hydride, sodium metal, lithium or sodium amide, potassium t-butoxide, lithium hexamethyldisilyl azide) in a suitable solvent such as ethanol, toluene, dioxane, tetrahydrofuran, 1,2-dichlorobenzene (or other aprotic solvent) or without any solvent at a temperature in the range between 20xc2x0 C. and the reflux temperature of the reaction mixture (March J., Advanced Organic Chemistry, J. Wiley, Chapter 10, 491-493, 1992; Schmutz, J., Helvetica Chimica Acta, 767-779, 1951). The intermediate crude xcex1,xcex3-diketoester is directly cyclized to 4 (Alk=C1-4 alkyl) by acid catalysis using an appropriate acid (e.g., 37% HCl, 98% H2SO4, glacial acetic acid, trifluoroacetic acid, perchloric acid) in an appropriate solvent such as ethanol, toluene, a chlorinated solvent, or without any solvent, at a temperature in the range between 20xc2x0 C. and the reflux temperature of the reaction mixture (Bryan J. D., J. Chem. Soc Perkin Trans. 1: 1279-1281, 1960). Hydrolysis of the ester function of 4, typically accomplished by acid or base catalysis using methods well known to those skilled in the art, affords Compounds 5. Such procedures include the use of sodium hydroxide in aqueous ethanol at 40-75xc2x0 C. or lithium hydroxide in aqueous dimethylformamide or dioxane or tetrahydrofuran at 40-100xc2x0 C.
Compounds 5 can be converted into keto derivatives 6 by direct reaction of lithium carboxylate with alkyl lithium derivatives (Rubottom G. M., J. Org. Chem. 48: 1550-1552, 1983). Alternatively, the carboxy group may be converted to keto derivatives by first converting the carboxy group into a more reactive C(O)X group, where X is 1-imidazolyl, chloro or bromo, OC(O)R or other reactive group, and then continuing the reaction with, for example, Meldrum""s acid to afford an enolacyl derivative that can be hydrolyzed with acetic acid to give 6 or, alternatively, with the magnesium salt of a suitable xcex2-diester (such as di-t-butyl malonate or diethyl malonate) to afford the corresponding xcex2-ketoester to be hydrolyzed to 6.
Oxidative cleavage of the exocyclic double bond may be accomplished by methods well known to those skilled in the art, as, for example, by permanganate oxidation or other oxidative method (see, for example, Haines A. H., Methods for the oxidation of organic compounds, Academic press, 1985, Chapter 3, part 5, 146-151) to yield the desired carboxylic acids 1 having R=C(O)Alk (Alk=C1-4 alkyl). Acids 1 in which R is a COOAlk (Alk=C1-4 alkyl) group can be clearly prepared from intermediates 4 carrying out the double-bond oxidation step as described above for 6.
Acids 1 in which R is a CONR1R2 group can be prepared from intermediates 5 through an amidification reaction, which is well known to those skilled in the art, such as that described for 1, with ammonia or an appropriate amine, and oxidation of the double-bond is carried out as described above. A preferred method of amidification under mild conditions includes conversion of 5 to the respective acyl chloride by the use of oxalyl chloride (EP 0625522, Sohda et al.).
Compounds I in which R is a cyano group be obtained from compounds I with R=CONH2 by a dehydration reaction through the use of triphenylphosphine in carbon tetrachloride or toluene or other suitable solvent at room temperaturexe2x80x94reflux or, more preferably, by the use of phosphorous-oxychloride/dimethylformamide or by other dehydration methods known to those skilled in the art (March J., Advanced Organic Chemistry, J. Wiley, Part 2, Chapter 7, part 39, 1041-1042, 1992).
Compounds I in which R is a NHCOOAlk (Alk=C1-4 alkyl) group can be prepared from intermediate 5 by Curtius rearrangement (March J., Advanced Organic Chemistry, 4th edition, J. Wiley, ed., pages 1091-1092, 1992) carried out with diphenylphosphoryl azide and triethylamine in an appropriate alkanol at reflux or in a mixture of acetonitrile (or other solvent) and the appropriate alkanol. Oxidation of these intermediates as above affords acids 1 with R=NHCOOAlk (Alk=C1-4 alkyl).
Compounds I in which R1 is a trifluoromethanesulphonyloxy group can be synthesized starting from compounds I in which R1 is a hydroxy group by procedures that include the use of trifluoromethanesulphonic anhydride or N-phenyltrifluoromethanesulphonimide in aprotic solvents such as 1,2-dichloroethane or other chlorinated solvents or toluene at a temperature in the range between xe2x88x9220xc2x0 C. and the reflux temperature of the solvent (Hendickson J. B., Tetrahedron Letters, 4607-4610, 1973).
The N-oxides of compounds I can be synthesized by simple oxidation procedures well known to those skilled in the art. The oxidation procedure described by P. Brougham et al. (Synthesis, 1015-1017, 1987), allows the two nitrogen of the piperazine ring to be differentiated, enabling both the N-oxides and N,Nxe2x80x2-dioxide to be obtained.
The preparation of phenylpiperazines 7 not yet disclosed in the literature is well documented in the experimental part and uses synthetic procedures well known to those skilled in the art, which comprise the synthesis of the proper aniline through well known reactions and the subsequent cyclization with bis-(2-chloroethyl)amine to afford the piperazine following the method of Prelog, Collect. Czech. Chem. Comm. 5: 497-502, 1933) or its variations (Elworthy T. R., J. Med. Chem. 40: 2674-2687, 1997).
Some examples are shown below to illustrate the invention as described in this text, with no intention to limit it.